Phenyl substituted pyridine and benzene derivatives

ABSTRACT

The present invention is a series of compounds formed from phenyl substituted pyridine or benzene derivatives and their pharmaceutically acceptable salts. These compounds have shown high affinity as antagonists to the NK-1 receptor.

This application is a divisional application of U.S. patent applicationSer. No. 09/505,356, filed Feb. 16, 2000 now U.S. Pat. No. 6,407,111.

BACKGROUND OF THE INVENTION

The neuropeptide receptor for Neurokinin 1 (substance P, NK-1) is widelydistributed throughout the mammalian nervous system (especially brainand spinal ganglia), the circulatory system and peripheral tissues(especially the duodenum and jejunum) and are involved in regulating anumber of diverse biological processes. Substance P is a naturallyoccurring undecapeptide belonging to the tachykinin family of peptides,the latter being so-named because of their prompt contractile action onextravascular smooth muscle tissue. The receptor for substance P is amember of the superfamily of G protein-coupled receptors.

The central and peripheral actions of the mammalian tachykinin,substance P, have been associated with numerous inflammatory conditionsincluding migraine, rheumatoid arthritis, asthma, and inflammatory boweldisease as well as mediation of the emetic reflex and the modulation ofcentral nervous system (CNS) disorders such as Parkinson's disease(Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75,612-621) and depression (Science, 1998, 281, 1640-1645).

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases is reviewed in “TachykininReceptor and Tachykinin Receptor Antagonists”, J. Auton. Pharmacol., 13,23-93, 1993.

Furthermore, Neurokinin 1 receptor antagonists are being developed forthe treatment of a number of physiological disorders associated with anexcess or imbalance of tachykinin, in particular substance P. Examplesof conditions in which substance P has been implicated include disordersof the central nervous system such as anxiety, depression and psychosis(WO 95/16679, WO 95/18124 and WO 95/23798).

The neurokinin-1 receptor antagonists are further useful for thetreatment of motion sickness and for treatment induced vomiting.

In addition, in The New England Journal of Medicine, Vol. 340, No. 3190-195, 1999 has been described the reduction of cisplatin-inducedemesis by a selective neurokinin-1-receptor antagonist.

Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating apsychoimmunologic or a psychosomatic disorder by administration of atachykinin receptor, such as NK-1 receptor antagonist.

SUMMARY OF THE INVENTION

In accordance with the present invention, the compounds of formula I andtheir salts are characterized by valuable therapeutic properties. It hasbeen surprisingly found that the compounds of the present invention areantagonists of the Neurokinin 1 (NK-1, substance P) receptor. Objects ofthe present invention are the compounds of formula I andpharmaceutically acceptable salts thereof, the preparation of theabove-mentioned compounds, medicaments containing them and theirmanufacture as well as the use of the above-mentioned compounds in thecontrol or prevention of illnesses, especially of illnesses anddisorders of the kind referred to earlier or in the manufacture ofcorresponding medicaments. The most preferred indications for treatmentin accordance with the present invention are those which includedisorders of the central nervous system or emesis, for example thetreatment or prevention of certain depressive disorders by theadministration of NK-1 receptor antagonists. A major depressive episodehas been defined as being a period of at least two weeks during which,for most of the day and nearly every day, there is either depressed moodor the loss of interest or pleasure in all, or nearly all activities.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula

wherein

R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;

R¹ is hydrogen or halogen; or

R and R¹ may be together —CH═CH—CH═CH—;

R² is hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;

R³ is, independently from each other, hydrogen, lower alkyl or form acycloalkyl group;

R⁴ is hydrogen, halogen, lower alkyl, lower alkoxy, —N(R⁵)₂,—N(R⁵)S(O)₂-lower alkyl, —N(R⁵)C(O)R⁵ or a cyclic tertiary amine of thegroup

R ⁵ is, independently from each other, hydrogen, C₃-₆-cycloalkyl, benzylor lower alkyl;

R⁶ is hydrogen, hydroxy, lower alkyl, —N(R⁵)CO-lower alkyl,hydroxy-lower alkyl, cyano, —CHO or a 5-or 6 membered heterocyclicgroup, optionally bonded via an alkylene group,

X is —C(O)N(R⁵)—, —(CH₂)_(m)O—, —(CH₂)_(m)N(R⁵)—, —N(R⁵)C(O)—, —C(O)O—or—N(R⁵)(CH₂)_(m)—;

Y is —(CH₂)_(n)—, —O—, —S—, —SO₂—, —C(O)— or—N(R⁵)—;

Z s═N—, —CH═ or —C(Cl)═;

n is 0-4; and

m is 1 or 2;

and to pharmaceutically acceptable acid addition salts thereof.

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

As used herein, the term “lower alkyl” denotes a straight- orbranched-chain alkyl group containing from 1-7 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl andthe like.

Preferred lower alkyl groups are groups with 1-4 carbon atoms.

The term “lower alkoxy” denotes a group wherein the alkyl residues areas defined above, and which is attached via an oxygen atom.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “cycloalkyl” denotes a saturated carbocyclic group, containing3-6 carbon atoms.

The term “cyclic tertiary amine” denotes, for example, pyrrol-1-yl,imidazol-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, 1-oxo-thiomorpholin-4-yl or1,1-dioxo-thiomorpholin-4-yl.

The term “5 or 6 membered heterocyclic group” denotes, for examplepyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl,thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,piperazinyl or piperidyl.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methanesulfonic acid, p-toluenesulfonic acid and the like.

Exemplary preferred are compounds, in which Y is —C(O)— and R⁴ is4-methylpiperazinyl, for example the following compounds:

N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,

4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamideand

N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide.

Further preferred are compounds, in which Y is —O— and R⁴ is hydrogen,morpholinyl or 4-methylpiperazinyl. Examples of such compounds are:

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenoxy-phenyl)-isobutyramide,

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-o-tolyloxy-phenyl)-isobutyramide,

2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(2,4-dichloro-phenoxy)-phenyl]-N-methyl-isobutyramide,

N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,

N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide,

N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamideand

N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide.

Further preferred are compounds, in which Y is —N(CH₃)— and R⁴ ishydrogen, for example the following compounds:

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamide,

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-isobutyramide,

2-(3,5-B is-trifluoromethyl-phenyl)-N-[2-(methyl-phenyl-amino)-phenyl]-acetamide and2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-acetamide.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below, which process comprises

reacting a compound of formula

with a compound of formula

to a compound of formula

wherein R¹-R⁵, R, Y, Z and n have the significances given above, or

b) reacting a compound of formula

with a compound of formula

to give a compound of formula

wherein R¹-R⁵, R, Z, Y and n have the significances given above, orreducing a compound of formula

to a compound of formula

wherein the definitions of substituents are given above, or

d) reacting a compound of formula

with a compound of formula

to a compound of formula

wherein the definitions of substituents are given above, or

e) reacting a compound of formula

with a compound of formula

to a compound of formula

wherein the definitions of substituents are given above, or

f) reducing a compound of formula

to a compound of formula

wherein the definitions of substituents are given above, or

g) reacting a compound of formula

with a compound of formula

to a compound of formula

wherein the definition of substituents is given above, or

h) reacting a compound of formula

with a compound of formula

to a compound of formula

wherein the definition of substituents is given above, or

i) reacting a compound of formula

with a compound of formula

to a compound of formula

wherein the definition of substituents is given above, or

j) modifying one or more substituents R¹-R⁵ or R within the definitionsgiven above, and

if desired, converting the compound obtained into a pharmaceuticallyacceptable acid addition salt.

In accordance with process variant a) a compound of formula II, forexample 3-amino-4-benzoylpyridine, is cooled in an ice bath and acompound of formula III, for example2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl propionyl chloride in thepresence of DIPEA (N-ethyldiisopropyl-amine) in dichloromethane isadded, and then the mixture is stirred at room temperature. The desiredcompound of formula I-1 is yielded after purification in good yields.

Process variant b) describes the reaction of a compound of formula IVwith a compound of formula V to a compound of formula I-2. The reactionis carried out in conventional manner, for example in a solvent, such asa mixture of toluene and triethyl-amine. The mixture is refluxed forabout 1 hour.

In accordance with process variant c) a compound of formula I-2 isreduced to a compound of formula I-4. This reaction is carried out witha reducing agent, such as LiAlH4 or BH3.THF, in conventional manner.

Process variant d) describes the reaction of a compound of formula VIwith a compound of formula VII to a compound of formula I-2. Thisreaction is carried out by deprotonation of a compound of formula VIwith KHMDS (potassium hexamethyldisilazide) and subsequent addition of acompound of formula VII. A suitable solvent is tetra-hydrofuran. Thereaction is carried out at room temperature.

In accordance with process variant e) a compound of formula I-5 isprepared. This reaction is carried out by deprotonation of a compound offormula VIII with NaH and subsequent addition of a compound of formulaVII. This reaction is carried out in conventional manner.

A further method for the preparation of a compound of formula I isdescribed in process variant f). A compound of formula I-1 is reduced toa compound of formula I-3 in conventional manner, for example withLiAlH4 or BH₃.THF.

In the process variant g) a compound of formula IX is activated with DCC(N,N′-dicyclohexylcarbodiimide) and DMAP (4-N,N-dimethylaminopyridine).Subsequent addition of a compound of formula X yields a compound offormula I-6.

In accordance with variant h) a compound of formula IX is activated withCDI (1,1′-carbonyldiimidazole) and subsequent addition of a compound offormula V gives a compound of formula I-2.

The process variant i) describes the process for preparation of acompound of formula I-1, wherein a compound of formula XII is activatedwith CDI and subsequent addition of a compound of formula II yields acompound of formula I-13.

The salt formation is effected at room temperature in accordance withmethods which are known per se and which are familiar to any personskilled in the art. Not only salts with inorganic acids, but also saltswith organic acids came into consideration. Hydrochlorides,hydrobromides, sulphates, nitrates, citrates, acetates, maleates,succinates, methan-sulphonates, p-toluenesulphonates and the like areexamples of such salts.

The following schemes 1-7 describe the processes for preparation ofcompounds of formula I in more detail. The starting materials offormulae IX, X, XI, II, III, XII, XIII, XV, XVII, XVIII, XX, XXII, XXIVand XXV are known compounds or may be prepared according to methodsknown in the art.

In the schemes the following abbreviations have been used:

DCC N,N′-dicyclohexylcarbodiimide DMAP 4-(N,N-dimethylamino)pyridine CDI1,1′-carbonyldiimidazole KHMDS potassium hexamethyldisilazide DIPEAN-ethyldiisopropyl-amine PivCl pivaloyl chloride

The substituents are given above.

The substituents are given above.

The definition of substituents is given above.

The definition of substituents is given above.

The definition of substituents is given above.

The definition of substituents is given above.

R, R¹, R², R³ and R⁵ have the significances given above.

As mentioned earlier, the compounds of formula I and theirpharmaceutically usable addition salts possess valuable pharmacologicalproperties. It has been found that the compounds of the presentinvention are antagonists of the Neurokinin 1 (NK-1, substance P)receptor.

The compounds were investigated in accordance with the tests givenhereinafter.

The affinity of test compounds for the NK1 receptor was evaluated athuman NK1 receptors in CHO cells infected with the human NK1 receptor(using the Semliki virus expression system) and radiolabelled with[3H]substance P (final concentration 0.6 nM). Binding assays wereperformed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%)leupeptin (8 mg/ml), MnCl2 (3 mM) and phosphoramidon (2 mM). Bindingassays consisted of 250 ml of membrane suspension (1.25×105 cells/assaytube), 0.125 ml of buffer of displacing agent and 125 ml of[3H]substance P. Displacement curves were determined with at least sevenconcentrations of the compound. The assay tubes were incubated for 60min at room temperature after which time the tube contents were rapidlyfiltered under vacuum through GF/C filters presoaked for 60 min with PEI(0.3%) with 2×2 ml washed of HEPES buffer (50 mM, pH 7.4). Theradioactivity retained on the filters was measured by scintillationcounting. All assays were performed in triplicate in at least 2 separateexperiments.

The affinity to the NK-1 receptor, given as pKi, is in the scope of7,50-9,00 for the preferred compounds. Examples for such compounds are

N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-7,86 nicotinamideN-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-8,42 methyl-piperazin-1-yl)-nicotinamideN-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-8,56 nicotinamideN-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6- 8,76morpholin-4-yl-nicotinamide

The compounds of formula I as well as their pharmaceutically usable acidaddition salts can be used as medicaments, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

The compounds of formula I and their pharmaceutically usable acidaddition salts can be processed with pharmaceutically inert, inorganicor organic excipients for the production of tablets, coated tablets,dragees and hard gelatine capsules. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts etc can be used as suchexcipients e.g. for tablets, dragées and hard gelatine capsules.Suitable excipients for soft gelatine capsules are e.g. vegetable oils,waxes, fats, semisolid and liquid polyols etc.

Suitable excipients for the manufacture of solutions and syrups are e.g.water, polyols, saccharose, invert sugar, glucose etc.

Suitable excipients for injection solutions are e.g. water, alcohols,polyols, glycerol, vegetable oils etc.

Suitable excipients for suppositories are e.g. natural or hardened oils,waxes, fats, semi-liquid or liquid polyols etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, in thecase of oral administration a daily dosage of about 10 to 1000 mg perperson of a compound of general formula I should be appropriate,although the above upper limit can also be exceeded when necessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

EXAMPLE 1

N-(4-Benzoyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

a)N-(4-Benzoyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide

A solution of 397 mg (2 mmol) 3-amino-4-benzoylpyridine and 517 mg (4mmol) N-ethyldiisopropylamine in 8 ml dichloromethane was cooled in anice bath and a solution of 765 mg (2.4 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 8 mldichloromethane was added dropwise. The reaction mixture was warmed toroom temperature and was stirred overnight. Water (5 ml) was added andthe organic layer was separated. The aqueous phase was extracted withdichloromethane. The combined organic layers were dried (magnesiumsulfate) and evaporated. The residue was purified by flashchromatography to give 235 mg (24%) of the title compound as orange oil.

MS m/e (%): 481.3 (M+H⁺, 100).

b)N-(2-Benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

To a solution of 96 mg (0.2 mmol) ofN-(4-benzoyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramidein 1.2 ml of dimethylformamide were added 0.22 ml of a 1M potassiumhexamethyldisilazide solution at 0° C. After 30 min 57 mg of methyliodide (0.4 mmol) were added and the reaction mixture was stirred atroom temperature overnight. The solvent was evaporated, water anddichloromethane were added to the residue, the organic layer wasseparated and dried over magnesium sulfate. After evaporation of thesolvent the product was purified by flash chromatography to yield 12 mg(12%) of the title compound as yellow oil.

MS m/e (%): 495.2 (M+H⁺, 100).

EXAMPLE 2

N-(2-Benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

a)N-(2-Benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide

To a solution of 233 mg (1 mmol) of 2-amino-5-chlorobenzophenone in 2 mlof 1,2-dichloroethane were added 360 mg (1.2 mmol) of2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid and thereaction mixture was shaken at 80° C. for 1 h. Dicyclohexyl carbodiimide(194 mg, 1.2 mmol) was added and shaking was continued overnight at thesame temperature. The solvent was evaporated and the residue obtainedwas purified by column chromatography on silica gel to yield 298 mg(58%) of the title compound as yellow oil.

MS m/e (%): 514.2 (M+H⁺, 100)

b)N-(2-Benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

To a solution of 154 mg (0.3 mmol) ofN-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramidein 1 ml dimethylformamide were added 26 mg (0.6 mmol) sodium hydride(55% suspension in mineral oil). After 30 min stirring at roomtemperature 85 mg of methyl iodide (0.6 mmol) were added and thereaction mixture was stirred at 80° C. overnight. The solvent wasevaporated under reduced pressure and the residue was purified by flashchromatography to yield 51 mg (32%) of the title compound as whitecrystals. M.p. 89-91° C.

MS m/e (%): 528.1 (M+H⁺, 100).

EXAMPLE 3

N-(2-Benzoyl-5-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as yellow oil in comparable yieldsaccording to the procedures described above for the preparation ofN-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-amino-4-chlorobenzophenone instead of2-amino-5-chlorobenzophenone.

MS m/e (%): 528.1 (M+H⁺, 100).

EXAMPLE 4

N-(2-Benzoyl-3-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as yellowish oil in comparable yieldsaccording to the procedures described above for the preparation ofN-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-amino-6-chlorobenzophenone instead of2-amino-5-chlorobenzophenone.

MS m/e (%): 528.1 (M+H⁺, 100).

EXAMPLE 5

2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(3-chloro-benzoyl)-phenyl]-N-methyl-isobutyramide

The title compound was obtained as yellow oil in comparable yieldsaccording to the procedures described above for the preparation ofN-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-(3-chlorobenzoyl)-aniline instead of2-amino-5-chlorobenzophenone.

MS m/e (%): 528.1 (M+H⁺, 100).

EXAMPLE 6

N-(2-Benzoyl-6-methoxy-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as yellow oil in comparable yieldsaccording to the procedures described above for the preparation ofN-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-amino-3-methoxybenzophenone instead of2-amino-5-chlorobenzophenone.

MS m/e (%): 523.5 (M+H⁺, 100).

EXAMPLE 7

N-(2-Benzoyl-4-methoxy-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as yellow oil in comparable yieldsaccording to the procedures described above for the preparation ofN-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-amino-5-methoxybenzophenone instead of2-amino-5-chlorobenzophenone.

MS m/e (%): 523.5 (M+H⁺, 100).

EXAMPLE 8

(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-chloro-2-(2-chloro-phenylsulfanyl)-phenyl]-N-methyl-propionamide

To a solution of 142 mg (0.5 mmol) of1-chloro-4-methylamino-3-(2-chloro-phenylsulfanyl)-benzene in 2 ml of1,2-dichloroethane were added 172 mg (0.6 mmol) of2-(3,5-bis-trifluoromethyl-phenyl)-propionic acid and the reactionmixture was shaken at 80° C. for 1 h. Dicyclohexyl carbodiimide (97 mg,0.6 mmol) was added and shaking was continued overnight at the sametemperature. The solvent was evaporated and the residue obtained waspurified by column chromatography on silica gel to yield 56 mg (20%) ofthe title compound as light yellow oil.

MS m/e (%): 551.9 (M+H⁺, 100), 553.9 (M+H⁺, 90).

EXAMPLE 9

(RS)-N-(2-Benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-propionamide

The title compound was obtained as yellow oil in comparable yieldsaccording to the procedures described above for the preparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-chloro-2-(2-chloro-phenylsulfanyl)-phenyl]-N-methyl-propionamideusing 2-methylamino-5-chlorobenzophenone instead of1-chloro-4-methylamino-3-(2-chloro-phenylsulfanyl)-benzene.

MS m/e (%): 514.2 (M+H⁺, 100).

EXAMPLE 10

N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramideHydrochloride (1:1)

a) 2,2-Dimethyl-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionamide

A solution of 5.58 g (29 mmol) 1-(4-aminophenyl)-4-methylpiperazine and3.77 g (29 mmol) N-ethyldiisopropylamine in 30 ml tetrahydrofuran wascooled in an ice bath and 3.518 g (29 mmol) pivaloyl chloride were addeddropwise. The suspension was stirred for 18 h at room temperature. Water(30 ml) and dichloromethane (50 ml) were added and the organic layer wasseparated. The aqueous phase was re-extracted with dichloromethane. Thecombined organic layers were dried (magnesium sulfate) and evaporated togive a white solid. Washing with a mixture of hexane and ethyl acetate(4:1) yielded 6.69 g (83%) of a white crystalline compound.

MS m/e (%): 276.3 (M+H⁺, 100).

b)N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2,2-dimethyl-propionamide

A solution of 1.375 g (5 mmol) of2,2-dimethyl-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionamide wasdissolved in 25 ml tetrahydrofuran and cooled to −70° C. Under argon 7.8ml (12.5 mmol) of a 1.6 M n-butyl lithium solution in hexane was addedslowly at this temperature. The cooling bath was removed and the mixturewas stirred for 3 h at room temperature. The reaction mixture was cooleddown again to −70° C. and a solution of 1.234 g N-methoxy-N-methylbenzamide (7.2 mmol) in 5 ml tetrahydrofuran was added slowly at −70° C.After 10 min the cooling bath was removed and stirring was continued atroom temperature for 1 hour. Water (50 ml) was added to quench thereaction and the mixture was extracted with diethylether (three times 50ml). The organic layer was dried with magnesium sulfate and evaporatedto give a brown oil, which was purified by flash chromatography withdichloromethane/methanol to yield 315 mg (17%)of the product as a lightorange solid.

MS m/e (%): 380.4 (M+H⁺, 100).

c) [2-Amino-5-(4-methyl-piperazin-1-yl)-phenyl]-phenyl-methanone

A solution of 0.3 g (0.8 mmol) ofN-[2-benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2,2-dimethyl-propionamidein 10 ml of 3 N aqueous hydrochloric acid was stirred for 20 h at roomtemperature. The reaction mixture was extracted once with ethyl acetate,the aqueous layer was made alkaline with concentrated sodium hydroxidesolution and was extracted four times with dichloromethane. The combinedorganic layers were dried over magnesium sulfate and evaporated to yield245 mg (quantitative) of the product as light yellow oil.

MS m/e (%): 296.4 (M+H⁺, 100).

d)N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramideHydrochloride

A solution of 200 mg (0.68 mmol)[2-amino-5-(4-methyl-piperazin-1-yl)-phenyl]-phenyl-methanone and 219 mg(1.69 mmol) N-ethyldiisopropylamine in 5 ml dichloromethane was cooledin an ice bath and a solution of 319 mg (1.0 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 2 mldichloromethane was added dropwise. The reaction mixture was warmed toroom temperature and was stirred for 3 hours. Water (5 ml) was added andthe layers were separated. The aqueous phase was re-extracted withdichloromethane. The combined organic layers were dried (magnesiumsulfate) and evaporated to give 50 mg of an oil. The residue wasdissolved in 2 ml of ethyl acetate and 0.018 ml of a 4.75 N solution ofhydrochloric acid in ethanol was added. After addition of 1 ml ofdiethylether the suspension was stirred for 15 min, the solid wasfiltered off and dried to give 24 mg (6%) of the title compound as awhite solid.

MS m/e (%): 578.1 (M+H⁺, 100).

EXAMPLE 11

4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamideHydrochloride (1:1)

a) 2-Chloro-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridineHydrochloride

To 10 g (63.47 mmol) 2-chloropyridine-5-carboxylic acid were added 60 g(507 mmol) thionylchloride and the mixture was refluxed for 3 h. Excessthionylchloride was distilled off, ether (50 ml) was added andevaporated to remove traces of thionylchloride. The residue wasdissolved in 30 ml dichloromethane and added dropwise to a solution of11.88 g (0.133 mmol) 2-amino-2-methylpropanol in 30 ml dichloromethaneat 0° C. The reaction mixture was stirred for 2 hours at roomtemperature and 30 ml water were added. The layers were separated andthe aqueous phase was extracted again with dichloromethane. The combinedorganic layers were dried with magnesium sulfate and evaporated to yieldan oily liquid. To the residue were added 22.6 g (190 mmol) ofthionylchloride at 0° C. and the mixture was stirred for 30 min. Ethylacetate was added, the mixture was stirred for another 30 min and thecrystals were washed with ethyl acetate and ether to yield 14 g (89%) ofa white solid.

MS m/e (%): 210 (M+H⁺, 10).

b)1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-pyridin-2-yl]-4-methyl-piperazine

2-Chloro-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridine hydrochloridewas transformed into its free base by dissolving 8.0 g (32 mmol) insaturated sodium bicarbonate solution and extracting the base intodichloromethane. The solvent was evaporated and the residue wasdissolved in toluene. After addition of 11.35 g (113 mmol)N-methylpiperazine, the mixture was refluxed for 36 h. After cooling toroom temperature water (50 ml) and ethyl acetate (150 ml) were added andthe aqueous layer was extracted with ethyl acetate (150 ml). Thecombined organic layers were extracted two times with 1 N hydrochloricacid, the acidic aqueous layer was made alkaline with 28% sodiumhydroxide solution and extracted two times with dichloromethane. Theorganic layer was dried (magnesium sulfate) and evaporated. The residuewas crystallized from ethyl acetate/hexane to yield 6.0 g (67%) of awhite crystalline compound.

MS m/e (%): 274.1 (M+H⁺, 100).

c)[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-phenyl-methanone

2,2,6,6-Tetramethylpiperidine (0.932 g, 6.6 mmol) was placed in athree-necked flask. Under argon 10 ml of hexane were added, the solutionwas cooled to 0° C. and n-butyl lithium (1.6 M solution in hexane) wasadded slowly. After stirring the yellow suspension for 10 min at 0° C.,N,N,N′,N′-tetramethylethylenediamine (767 mg, 6.6 mmol) was added. Thismixture was added dropwise to a suspension of 1.65 g (6 mmol) of1-[5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridin-2-yl]-4-methyl-piperazinein 20 ml of hexane at −78°. After stirring the yellow solution for 30min at this temperature and for 45 min at 0° C., a solution of 1.19 gN-methoxy-N-methyl benzamide (7.2 mmol) in 2 ml hexane/2 mltetrahydrofuran was added slowly at 0° C. After 30 min, the cooling bathwas removed and stirring was continued at room temperature overnight.Water was added and the mixture was extracted with ethyl acetate. Theorganic layer was dried (magnesium sulfate) and evaporated to give abrown oil, which was purified by flash chromatography withdichloromethane/methanol to yield 1.16 g (51%) of the product as ayellow solid.

MS m/e (%): 379.5 (M+H⁺, 100).

d) 4-Benzoyl-6-(4-methyl-piperazin-1-yl)-nicotinic acid2-amino-2-methyl-propyl Ester

To a solution of 1.13 g (3 mmol)[5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-phenyl-methanonein 30 ml tetrahydrofuran were added 3 ml of 2 N aqueous hydrochloricacid and the reaction mixture was heated at 50° C. for 18 h. Aftercooling to room temperature, 1 N sodium hydroxide solution was added toadjust pH 11 and the mixture was extracted with ethyl acetate. Theorganic layer was dried (magnesium sulfate) and evaporated to yield 1.18g (quantitative) of the product as yellow oil.

MS m/e (%): 481.4 (M+H^(+,) 100).

e) 4-Benzoyl-6-(4-methyl-piperazin-1-yl)-nicotinic Acid

To a solution of 1.15 g (2.9 mmol) of4-benzoyl-6-(4-methyl-piperazin-1-yl)-nicotinic acid2-amino-2-methyl-propyl ester in 20 ml tetrahydrofuran were addeddropwise 367 mg (3.05 mmol) pivaloyl chloride at 0° C. After stirringthe light yellow suspension at the same temperature for 1 hour, 1 Maqueous hydrochloric acid was added. Excess pivaloyl chloride wasextracted with dichloromethane, the aqueous layer was made alkaline with28% sodium hydroxide solution and extracted twice with dichloromethane.The organic layer was dried (magnesium sulfate) and evaporated. Theresidue was dissolved in methanol, 1 M aqueous sodium hydroxide solutionwas added slowly at 0° C. and the mixture was heated overnight at 65° C.Methanol was evaporated and the aqueous layer was adjusted to pH 5. Thesolvent was evaporated to yield the product contaminated with sodiumchloride, which was used for the next step without further purification.

f)4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamideHydrochloride (1:1)

A mixture of 4-benzoyl-6-(4-methyl-piperazin-1-yl)-nicotinic acid (1.5mmol) from the last step and 3 ml of thionyl chloride were heated to110° C. for 1 hour. Excess of thionyl chloride was evaporated, the brownoil obtained was re-dissolved in ether and evaporated again to removetraces of thionyl chloride. The residue was dissolved in 2 ml of acetoneand 1.16 g (4.5 mmol) (3,5-bis-trifluoromethylbenzyl)-methyl-amine wereadded. The mixture was stirred for 1.5 h at room temperature. Thesolvent was evaporated, dichloromethane and water were added and theaqueous layer was made alkaline with sodium hydroxide solution (28%).The organic layer was dried (magnesium sulfate), evaporated and purifiedby flash chromatography to yield 202 mg of an oil. This compound wasdissolved in 5 ml diethyl ether and 0.075 ml of 4.75 N hydrochloric acidsolution in ethanol were added. After stirring for 15 min the suspensionwas evaporated to dryness, re-suspended in 10 ml diethyl ether, filteredand dried to give 190 mg (21%) of the title compound as a white solid.M.p. 105° C., (decomp.).

MS m/e (%): 565.2 (M+H⁺, 100).

EXAMPLE 12

N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamideHydrochloride (1:1)

The title compound was obtained as white crystals in comparable yieldsaccording to the procedures described above for the preparation of4-benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamidehydrochloride (1:1 using N-methoxy-N-methyl 2-chloro-benzamide insteadof N-methoxy-N-methyl benzamide in step c). M.p. 145° C., (decomp.).

MS m/e (%): 599.1 (M+H⁺, 100).

EXAMPLE 13

2-Phenoxy-benzoic acid 3,5-bis-trifluoromethyl-benzyl Ester

To a solution of 118 mg (0.55 mmol) 2-phenoxybenzoic acid and 122 mg(0.50 mmol) 3,5 bis(trifluoromethyl)benzyl alcohol in 1.5 mldichloromethane at 0° C. was added a solution of 124 mg (0.60 mmol)1,3-dicyclohexylcarbodiimide and 7 mg (0.06 mmol)4-dimethylaminopyridine in 1 ml dichloromethane. The ice bath wasremoved and stirring was continued at room temperature overnight. Thesolvent was removed in vacuo and the residue re-dissolved in diethylether, filtered and evaporated. The residue was purified by flashchromatography to give 70 mg (32%) of the title compound as whitecrystals.

MS m/e (%): 440 (M⁺, 51), 347 (39), 227 (36), 197 (100).

EXAMPLE 14

2-Benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-benzamide

To a solution of 255 mg (1.2 mmol) 2-benzylbenzoic acid in 1.5 mltetrahydrofuran at 0° C. were added 195 mg (1.2 mmol)1,1′-carbonyldiimidazole. After stirring for 2.5 h at room temperature,a solution of 243 mg (1.0 mmol) 3,5 bis(trifluoromethyl)benzylamine in0.5 ml tetrahydrofuran was added and stirring was continued overnight.The solvent was removed in vacuo and the residue was purified by flashchromatography to give 210 mg (49%) of the title compound as whitecrystals.

MS m/e (%): 438 (M+H⁺, 100).

EXAMPLE 15

2-Benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-benzamide

To a solution of 100 mg (0.23 mmol)2-benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-benzamide in 1 mlN,N-dimethylformamide at 0° C. were added 50 mg (0.25 mmol) potassiumhexamethyldisilazide. Stirring was continued for 1 h at this temperatureand 0.016 ml (0.25 mmol) methyl iodide were added. After stirring for 3h at room temperature, ethyl acetate was added. The mixture was washedwith brine, dried (magnesium sulfate) and evaporated. The solvent wasremoved in vacuo and the residue was purified by flash chromatography togive 90 mg (87%) of the title compound as a colourless oil.

MS m/e (%): 452 (M+H⁺, 100).

EXAMPLE 16

N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-2(methyl-phenyl-amino)-benzamide

a) N-(3,5-Bis-trifluoromethyl-benzyl)-2-phenylamino-benzamide

The title compound was obtained as white crystals in comparable yieldaccording to the procedure described above for the preparation of2-benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-benzamide.

MS m/e (%): 477 (M+K⁺, 24), 461 (M+Na⁺, 40), 439 (M+H⁺, 100).

b) 2-Benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-benzamide

The title compound was obtained as a colourless oil in comparable yieldaccording to the procedure described above for the preparation of2-benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-benzamide.

MS m/e (%): 505 (M+K⁺, 12), 489 (M+Na⁺, 19), 467 (M+H⁺, 100).

EXAMPLE 17

N-(2-Benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

a)N-(2-Benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide

A solution of 233 mg (1.0 mmol) 2-aminophenyl phenyl sulfone and 0.25 ml(1.5 mmol) N-ethyldiisopropylamine in 2 ml dichloromethane was cooled inan ice bath and a solution of 350 mg (1.1 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 mldichloromethane was added dropwise. The reaction mixture was stirred atroom temperature overnight, evaporated and the residue was purified byflash chromatography to give 490 mg (95%) of the title compound as apale yellow oil.

MS m/e (%): 533 (M+NH₄ ⁺, 60), 516 (M+H⁺, 100).

b)N-(2-Benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a colourless oil in comparable yieldaccording to the procedure described above for the preparation of2-benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-benzamide.

MS m/e (%): 552 (M+Na⁺, 40), 530 (M+H⁺, 100).

EXAMPLE 18

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenoxy-phenyl)-isobutyramide

The title compound was obtained as a colourless oil in comparable yieldaccording to the procedures described above for the preparation ofN-(2-benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-phenoxyaniline instead of 2-aminophenyl phenyl sulfone.

MS m/e (%): 482 (M+H⁺, 100).

EXAMPLE 19

N-(2-Benzyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a colourless oil in comparable yieldaccording to the procedures described above for the preparation ofN-(2-benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-benzylaniline instead of 2-aminophenyl phenyl sulfone.

MS m/e (%): 480 (M+H⁺, 100).

EXAMPLE 20

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-o-tolyloxy-phenyl)-isobutyramide

The title compound was obtained as pale yellow crystals in comparableyield according to the procedures described above for the preparation ofN-(2-benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-(o-tolyloxy)aniline instead of 2-aminophenyl phenyl sulfone.

MS m/e (%): 496 (M+H⁺, 100).

EXAMPLE 21

N-(2-Benzoyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a pale yellow oil in comparable yieldaccording to the procedures described above for the preparation ofN-(2-benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-aminobenzophenone instead of 2-aminophenyl phenyl sulfone.

MS m/e (%): 516 (M+Na⁺, 55), 494 (M+H⁺, 100).

EXAMPLE 22

2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(2,4-dichloro-phenoxy)-phenyl]-N-methyl-isobutyramide

The title compound was obtained as a colourless foam in comparable yieldaccording to the procedures described above for the preparation ofN-(2-benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-(2,4-dichlorophenoxy)aniline instead of 2-aminophenyl phenylsulfone.

MS m/e (%): 549 (M⁺, 4), 530 (21), 388 (100).

EXAMPLE 23

2-(3,5-Bis-trifluoromethyl-phenyl)-N-(2-phenylsulfanyl-phenyl)-isobutyramide

The title compound was obtained as a pale yellow oil in comparable yieldaccording to the procedure described above for the preparation ofN-(2-benzenesulfonyl-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing 2-aminophenyl phenyl sulfide instead of 2-aminophenyl phenylsulfone. Step b) was not performed.

MS m/e (%): 484 (M+H⁺, 100).

EXAMPLE 24

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamide

a) 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(2-phenylamino-phenyl)-acetamide

To a solution of 545 mg (2.0 mmol) 3,5-bis(trifluoromethyl)phenylaceticacid in 2 ml tetrahydrofuran at 0° C. were added 325 mg (2.0 mmol)1,1′-carbonyldiimidazole. After stirring for 2.5 h at room temperature,305 mg (1.66 mmol) 2-aminodiphenylamine were added and stirring wascontinued for 8 h at 60° C. The solvent was removed in vacuo and theresidue was purified by flash chromatography to give 480 mg (66%) of thetitle compound as white crystals.

MS m/e (%): 439 (M+H⁺, 35), 142 (100).

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamide

To a solution of 389 mg (0.89 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-(2-phenylamino-phenyl)-acetamide in1 ml N,N-dimethylformamide at 0°C. were added 560 mg (2.66 mmol)potassium hexamethyldisilazide. Stirring was continued for 1 h at thistemperature and 510 mg (2.66 mmol) methyl iodide were added. Afterstirring for 3 h at room temperature, ethyl acetate was added. Themixture was washed with brine, dried (magnesium sulfate) and evaporated.The solvent was removed in vacuo and the residue was purified by flashchromatography to give 110 mg (25%) of the title compound as whitecrystals.

MS m/e (%): 480 (M⁺, 76), 239 (100).

EXAMPLE 25

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-isobutyramide

To a solution of 52 mg (0.11 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamidein 0.5 ml N,N-dimethylformamide at 0° C. were added 32 mg (0.16 mmol)potassium hexamethyldisilazide. Stirring was continued for 1 h at thistemperature and 30 mg (0.16 mmol) methyl iodide were added. Afterstirring for 3 h at room temperature, ethyl acetate was added. Themixture was washed with brine, dried (magnesium sulfate) and evaporated.The solvent was removed in vacuo and the residue was purified by flashchromatography to give 54 mg (quantitative) of the title compound ascolourless oil.

MS m/e (%): 494 (M⁺, 87), 195 (100).

EXAMPLE 26

2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(methyl-phenyl-amino)-phenyl]-acetamide

The title compound was obtained as white crystals in comparable yieldaccording to the procedure described above for the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamideusing N-methyl-N-phenyl-benzene-1,2-diamine instead of2-aminodiphenylamine. Step b) was not performed.

MS m/e (%): 453 (M+H⁺, 100).

EXAMPLE 27

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-acetamide

The title compound was obtained as a colourless oil in comparable yieldaccording to the procedure described above for the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamideusing N,N′-dimethyl-N-phenyl-benzene-1,2-diamine instead of2-aminodiphenylamine. Step b) was not performed.

MS m/e (%): 467 (M+H⁺, 100).

EXAMPLE 28

N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide

a) 6-Chloro-4-phenoxy-nicotinic Acid Ethyl Ester

To a solution of 196 mg (ca. 4 mmol) sodium hydride dispersion inmineral oil (ca. 50%) in 15 ml N,N-dimethylformamide a solution of 385mg (4.09 mmol) phenol in 10 ml N,N-dimethylformamide was added dropwiseat room temperature under argon. After 15 min. this solution was slowlyadded via cannula to a solution of 4,6-dichloro-nicotinic acid ethylester in 20 ml N,N-dimethylformamide at room temperature. After 2 h thereaction was quenched with 20 ml water. The mixture was extracted with 350-ml portions of ethyl acetate. The combined organic extracts weredried with sodium sulfate and concentrated. After drying in high vacuoat 50° C. and flash column chromatography 800 mg (70.4%) of the titlecompound was obtained as a white solid. As a side product 130 mg (11.4%)4-chloro-6-phenoxy-nicotinic acid ethyl ester were also isolated.

MS m/e (%): 277 (M⁺, 81), 232 ([M-OEt]⁺, 100).

b) 6-Morpholin-4-yl-4-phenoxy-nicotinic Acid Ethyl Ester

A solution of 130 mg (0.468 mmol) 6-chloro-4-phenoxy-nicotinic acidethyl ester, 0.040 ml (0.47 mmol) morpholine and 0.065 ml (0.47 mmol)triethylamine in 7 ml tetrahydrofuran was stirred at reflux for 40 h.After cooling to room temperature the reaction mixture was filtered,diluted with ethyl acetate and washed with water and saturated aqueoussodium chloride solution. The organic layer was dried with sodiumsulfate and concentrated. Flash column chromatography afforded 66 mg(43%) of the title compound as a white solid.

MS m/e (%): 329 (M+H⁺, 100).

c) 6-Morpholin-4-yl-4-phenoxy-nicotinic Acid

A mixture of 66 mg (0.20 mmol) 6-morpholin-4-yl-4-phenoxy-nicotinic acidethyl ester, 2 ml methanol and 2 ml 1N aqueous sodium hydroxide solutionwas stirred at room temperature for 1 h. The reaction mixture wasdiluted with water and washed with tert-butyl-methyl-ether. The aqueouslayer was acidified to pH 4-5 with concentrated hydrochloric acidsolution and extracted with 3 portions of dichloromethane. The combinedorganic layers were washed with saturated aqueous sodium chloridesolution and dried with sodium sulfate. Concentration afforded 46 mg(77%) of the title compound as a white solid.

MS m/e (%): 301 (M+H⁺, 100).

d)N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide

A mixture of 46 mg (0.15 mmol) 6-morpholin-4-yl-4-phenoxy-nicotinicacid, 43 mg (0.17 mmol) (3,5-bis-trifluoromethyl-benzyl)-methylamine, 32mg (0.17 mmol) 1-(3-diaminopropyl)-3-ethyl-carbodiimide hydrochlorideand a catalytic amount of 4-(N,N-dimethylamino)-pyridine in 3 mldichloromethane was stirred at room temperature over night. The reactionmixture was diluted with water, adjusted to pH 6 with saturated aqueousammonium chloride solution and extracted with dichloromethane. Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried with sodium sulfate and concentrated. Flashcolumn chromatography afforded 68 mg (83%) of the title compound as awhite solid.

MS m/e (%): 540 (M+H⁺, 100).

EXAMPLE 29

N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide

The title compound was obtained as a white solid in comparable yieldsaccording to the procedures described above for the preparation ofN-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide(Example 28) using 2-chlorophenol instead of phenol in step a).

MS m/e (%): 574 (M+H⁺, 100).

EXAMPLE 30

N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide

The title compound was obtained as a white solid in comparable yieldsaccording to the procedures described above for the preparation ofN-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide(Example 28) using 2-chlorophenol instead of phenol in step a) and1-methylpiperazine instead of morpholine in step b).

MS m/e (%): 587 (M+H⁺, 100).

EXAMPLE 31

N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide

The title compound was obtained as a white solid in comparable yieldsaccording to the procedures described above for the preparationN-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide(Example 28) using o-cresol instead of phenol in step a).

MS m/e (%): 554 (M+H⁺, 100).

Table 1 sets for the the subtituents for each compound of the previouslydescribed Examples.

TABLE 1 Example No. R R¹ R² R³ X Y R⁴ Z 1 H H 3,5-CF₃ CH₃/CH₃—N(CH₃)C(O)— —C(O)— H ═N— 2 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —C(O)— 4-Cl—CH═ 3 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —C(O)— H —CHCH₃— 4 H H 3,5-CF₃CH₃/CH₃ —N(CH₃)C(O)— —C(O)— 3-Cl —CH═ 5 H 3-Cl 3,5-CF₃ CH₃/CH₃—N(CH₃)C(O)— —C(O)— H —CH═ 6 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —C(O)—6-OCH₃ —CH═ 7 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —C(O)— 4-OCH₃ —CH═ 8 Cl H3,5-CF₃ H/CH₃ —N(CH₃)C(O)— —S— 4-Cl —CH═ 9 H H 3,5-CF₃ H/CH₃—N(CH₃)C(O)— —C(O)— 4-Cl —CH═ 10 H H 3,5-CF₃ CH₃/CH₃ —NH—C(O)— —C(O)—

—CH═ 11 H H 3,5-CF₃ H/H —C(O)—N(CH₃)— —C(O)—

—N═ 12 Cl H 3,5-CF₃ H/H —C(O)—N(CH₃)— —C(O)—

—N═ 13 H H 3,5-CF₃ H/H —C(O)—O— —O— H —CH═ 14 H H 3,5-CF₃ H/H —C(O)—NH——CH₂— H —CH═ 15 H H 3,5-CF₃ H/H —C(O)—N(CH₃)— —CH₂— H —CH═ 16 H H3,5-CF₃ H/H —C(O)—N(CH₃)— —N(CH₃)— H —CH═ 17 H H 3,5-CF₃ CH₃/CH₃—N(CH₃)C(O)— —S(O)₂— H —CH═ 18 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —O— H—CH═ 19 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —CH₂— H —CH═ 20 CH₃ H 3,5-CF₃CH₃/CH₃ —N(CH₃)C(O)— —O— H —CH═ 21 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)——C(O)— H —CH═ 22 Cl 4-Cl 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —O— H —CH═ 23 H H3,5-CF₃ CH₃/CH₃ —NH—C(O)— —S— H —CH═ 24 H H 3,5-CF₃ CH₃/H —N(CH₃)C(O)——N(CH₃)— H —CH═ 25 H H 3,5-CF₃ CH₃/CH₃ —N(CH₃)C(O)— —N(CH₃)— H —CH═ 26 HH 3,5-CF₃ H/H —NH—C(O)— —N(CH₃)— H —CH═ 27 H H 3,5-CF₃ H/H —N(CH₃)C(O)——N(CH₃)— H —CH═ 28 H H 3,5-CF₃ H/H —C(O)—N(CH₃)— —O—

—N═ 29 H 2-Cl 3,5-CF₃ H/H —C(O)—N(CH₃)— —O—

—N═ 30 H 2-Cl 3,5-CF₃ H/H —C(O)—N(CH₃)— —O—

—N═ 31 H 2-CH₃ 3,5-CF₃ H/H —C(O)—N(CH₃)— —O—

—N═

EXAMPLE A

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn Starch 15 Microcrystallinecellulose 34 Magnesium stearat 1 Tablet weight: 100

EXAMPLE B

Capsules of the following composition are manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight: 200

The active substance, lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer, the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into hard gelatine capsules.

EXAMPLE C

Suppositories of the following composition are manufactured:

mg/supp. Active substance  15 Suppository mass 1285 Total 1300

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered activesubstance is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository moulds of suitablesize, left to cool, the suppositories are then removed from the mouldsand packed individually in wax paper or metal foil.

What is claimed is:
 1. A compound of the general formula

wherein R is hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R¹ is hydrogen or halogen; or R and R¹ may be together—CH═CH—CH═CH—; R² is hydrogen, halogen, trifluoromethyl, lower alkoxy orcyano; R³ is independently from each other hydrogen, lower alkyl or forma cycloalkyl group; R⁴ is hydrogen, halogen, lower alkyl, or loweralkoxy; R⁵ is, independently from each other, hydrogen, C₃-₆-cycloalkyl,benzyl or lower alkyl; X is —N(R⁵)C(O); Y is —O—, —S—, or —SO₂; Z is—CH═ or —C(Cl)═; and n is 0-4; and pharmaceutically acceptable acidaddition salts thereof.
 2. A compound according to claim 1, wherein Y is—O—, and R⁴ is hydrogen.
 3. A compound according to claim 2,2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenoxy-phenyl)-isobutyramide.4. A compound according to claim 2,2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-o-tolyloxy-phenyl)-isobutyramide.5. A compound according to claim 2,2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(2,4-dichloro-phenoxy)-phenyl]-N-methyl-isobutyramide.6. A pharmaceutical composition comprising: a compound of the followingformula I

 wherein R is hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R¹ is hydrogen or halogen; or R and R¹ may be together—CH═CH—CH═CH—; R² is hydrogen, halogen, trifluoromethyl, lower alkoxy orcyano; R³ is independently from each other hydrogen, lower alkyl or forma cycloalkyl group; R⁴ is hydrogen, halogen, lower alkyl, or loweralkoxy; R⁵ is, independently from each other, hydrogen, C₃-₆-cycloalkyl,benzyl or lower alkyl; X is —N(R⁵)C(O); Y is —O—, —S—, or —SO₂—; Z is—CH═ or —C(Cl)═; and n is 0-4; and pharmaceutically acceptable acidaddition salts thereof; and a pharmaceutically acceptable carrier orexcipient.
 7. A method of treating a disease mediated by modulation ofthe Neurokinin 1 receptor comprising administering, to a patient in needthereof, a therapeutically effective amount of a compound of formula I

wherein R is hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R¹ is hydrogen or halogen; or R and R¹ may be together—CH═CH—CH═CH—; R² is hydrogen, halogen, trifluoromethyl, lower alkoxy orcyano; R³ is independently from each other hydrogen, lower alkyl or forma cycloalkyl group; R⁴ is hydrogen, halogen, lower alkyl, or loweralkoxy; R⁵ is, independently from each other, hydrogen, C₃-₆-cycloalkyl,benzyl or lower alkyl; X is —N(R⁵)C(O); Y is —O—, —S—, or —SO₂—; Z is—CH═ or —C(Cl)═; and n is 0-4; and pharmaceutically acceptable acidaddition salts thereof.